Oncolytic viruses as therapeutic cancer vaccines - PubMed (original) (raw)

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Oncolytic viruses as therapeutic cancer vaccines

David L Bartlett et al. Mol Cancer. 2013.

Abstract

Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines.

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Figures

Figure 1

Figure 1

ICD of cancer cells induced by OVs leads to antitumor immunity. An OV, delivered either intratumorally or systemically, reaches to tumor tissue and selectively replicates in tumor or/and stromal cells. This leads to induction of death of these cells, presenting “eat me” signals on the cell surface and later release of danger signals from necrotic cells. Apoptotic bodies are engulfed by APC, and TAAs are processed and presented along with MHC complex and costimulatory molecules. The released DAMPs (and PAMPs) activate and mature DCs, and TAAs are cross-presented to naive T cells. This process can be further enhanced at different steps by other immunomodulatory agents (in a combination strategy). The resulting cytotoxic immune response against tumor and associated stromal cells, involving CD4+ and CD8+ T cells, may help in complete eradication of tumor mass. Additional immunotherapies targeting DCs, T cells, and the immunosuppressive TME can further enhance this antitumor immune response.

Figure 2

Figure 2

A model of how TILs in the TME are rescued to exert their effector functions by TLR ligands-reactivated DCs in the TME. TILs activated by oncolytic virotherapy or other cancer vaccines migrated from lymph nodes to the tumor tissues may require in situ activation by tumor–infiltrated DCs. However, the tumor-infiltrated DCs (TIDCs) are immunologically suppressed in the TME, but can be activated by TLR ligands or/and other TLR3/9 ligands (TLR ligands) through type I IFN-dependent signaling. Some OVs themselves or their products (such as dsRNA) can function as TLR ligands. The functionally reactivated TIDCs can acquire, process, and present TAAs to reactivate TILs to exert their functions. This model is modified from Xiao H et al., 2013 [153].

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